Abstract
Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-Å resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed “two-end” model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential.
We thank Craig Ogata for synchrotron beamline assistance. Beamline X4A at the National Synchrotron Light Source, a Department of Energy facility, is supported by the Howard Hughes Medical Institute. We are grateful to Irma Thesleff for advice and inspiration in calvaria culture, to Tilmann Wurtz for the osteocalcin probe, and to Daniel Bar-Shalom and BM Research (Denmark) for providing SOS. We thank Omar Ibrahimi for critical reading of the manuscript.
This work was supported by grants from the National Institutes of Health (DE-13686 to M.M.; HL-62244 and HL-52622 to R.J.L.), the Swedish Medical Research Council (2789 and 14100 to A.G.L.), and the Jubileum Kliniken (to A.G.L.).